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Theranostics 2017; 7(15):3759-3767. doi:10.7150/thno.20734 This issue Cite

Research Paper

Dual Functioned Pegylated Phospholipid Micelles Containing Cationic Antimicrobial Decapeptide for Treating Sepsis

Wonhwa Lee^*, Eun Ji Park^*, Gahee Min, Joonhyeok Choi, Dong Hee Na^#, Jong-Sup Bae^✉

College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics Based Creative Drug Research Team, Kyungpook National University, Daegu 41566, Republic of Korea
* First two authors contributed equally to this work.
# Current address; College of Pharmacy, Chung-Ang University, 84 Heukseok-ro, Dongjak-gu, Seoul 06974, Republic of Korea

✉ Corresponding author: Jong-Sup Bae, Ph.D., College of Pharmacy, Kyungpook National University, 80 Daehak-ro, Buk-gu, Daegu 41566, Republic of Korea Phone: 82-53-950-8570; Fax: 82-53-950-8557; E-mail: baejsac.kr

Abstract

Despite intensive investigation of molecular mechanisms underlying the pathogenesis of sepsis, many aspects of sepsis remain unresolved; this hampers the development of appropriate therapeutics. In the present study, we developed a biologic nanomedicine containing a cationic antimicrobial decapeptide KSLW (KKVVFWVKFK), self-associated with biocompatible and biodegradable PEGylated phospholipid micelles (PLM), and analyzed its efficacy for treating sepsis. KSLW was modified with polyethylene glycol (PEG)-aldehyde or was conjugated with distearoylphosphatidylethanolamine (DSPE) -PEG-aldehyde. We compared the antibacterial and antiseptic effects of PEG-KSLW and PLM-KSLW with those of unmodified KSLW both in vitro and in vivo. We found that the PLM-KSLW improved the survival rate of sepsis mouse models without undesired immune responses, and inhibited lipopolysaccharide (LPS)-induced severe vascular inflammatory responses in human umbilical vein endothelial cells compared with unmodified KSLW or PEG-KSLW. Furthermore, PLM-KSLW dramatically reduced the bacterial count and inhibited bacterial growth. We also found a new role of PLM-KSLW in tightening vascular barrier integrity by binding to the glycine/tyrosine-rich domain of occludin (OCLN). Our results showed that PLM-KSLW had a more effective antiseptic effect than KSLW or PEG-KSLW, possibly because of its high affinity toward OCLN. Moreover, PLM-KSLW could be potentially used to treat severe vascular inflammatory diseases, including sepsis and septic shock.

Keywords: sepsis, KSLW, PEGylation, DSPE, occluding.

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